During retinal development, progenitors undergo transitions from a proliferative state and then differentiate. The changes in development potential that accompany these transitions are tightly coordinated, although the mechanisms are not well understood. Disruption of these processes can result in failure of normal eye development, leading to severe eye disorders. Mutations in Sox2 have been linked to anopthalmia, and we have previously shown that Sox2 is critical for neural competence and initiation of proneural gene expression during retinal development. Our preliminary data indicates Sox2 is required for the differentiation of retinal progenitors; however, the precise role(s) that Sox2 plays in coordinating these events and how its function is regulated is not clear. Here we propose to address the roles of two important signaling pathways in the regulation of Sox2 and retinal neurogenesis. In Specific Aim 1, we will investigate the role of Wnt signaling on the expression of Sox2 and how this affects the expression and function of genes involved in retinal neurogenesis. In Specific Aim 2, we will analyze the role of Notch both in relationship to Sox2 and to Wnt signaling. The experiments outlined in this proposal will provide insight into the complex roles that Sox2 and Wnt signaling play in controlling the balance between proliferation and differentiation during vertebrate neurogenesis. In the longer term, by understanding how genes such as Sox2 coordinate the processes by which progenitors undergo developmental transitions, we will be better able to manipulate retinal stem cells or progenitors for treatment of retinal degenerative disease. [unreadable] [unreadable] [unreadable]